1. Field of the Invention
This invention relates generally to transgenic non-human animals which express a gene not naturally occurring in the animal. More specifically, the invention relates to transgenic non-human animals which express human prostate specific antigen.
2. Description of Related Art
Prostate cancer is the second leading cause of cancer deaths in American men. Although this disease is rarely seen in men under the age of 50, the incidence of prostate cancer increases rapidly in subsequent decades of life. Surgery, radiation and hormonal therapies are the standard treatments for prostate cancer, however, these conventional therapies ultimately are ineffective for metastatic disease. Immunotherapy mediated through cytotoxic T lymphocytes (CTL) offers a promising treatment avenue, since T cells, in principle, can migrate throughout the body and specifically recognize and destroy metastatic tumor cells in an antigen specific manner.
Prostate cancer cells express a well characterized antigen, prostate-specific antigen (PSA), whose expression is widely used clinically as a marker for prostate cancer. PSA, a kallikrein with serine protease activity, has a highly restricted tissue distribution and is expressed in the normal epithelial cells of the prostate gland, the same cell type from which most prostate tumors arise. Neither the regulation of PSA expression nor the role of PSA in normal or neoplastic prostate cells is well understood.
An obvious concern in using PSA as a target antigen for immunotherapy is that it is a self-antigen. To date, much of the work on tumor immunotherapy has implicitly assumed that it is necessary to identify and characterize antigens that are specifically and uniquely expressed in tumors but not in normal tissues. However, this assumption may not be warranted. For example, recent work has revealed that many targets for anti-melanoma CTL, such as tyrosinase, MART-1, gp100 and gp75, are normal self-antigens specific to the melanocyte lineage (V. Brichard et al., J. Exp. Med. 178:489-495, 1993; A. B. Bakker et al., J. Exp. Med. 179:1005-1009, 1994; S. L. Topalian et al., Proc. Natl. Aca. Sci USA 91:3515-3519, 1994; R. F. Wang et al., J. Exp. Med. 181:799-804, 1995). Further, the existence of a number of tissue-specific autoimmune diseases supports the concept that self-reactive immune effectors can be activated under appropriate conditions. Taken together, these findings raise the possibility that tissue-specific differentiation antigens could serve as targets for immunotherapy for other cancers besides melanoma. Thus, it may not be necessary to first isolate anti-tumor CTL from patients in order to identify the target antigens for characterization. Instead, it may be possible to induce a cell-mediated immune response against a normal tissue-specific antigen whether or not such responses typically occur in patients.
The study of PSA as a potential target antigen for immunotherapy, as well as other studies investigating its physiologic role, has been hampered by the lack of appropriate animal models. There is no currently available mouse system to model the salient immunological aspects of prostate cancer, as no prostate-specific kallikrein has been reported for mice.